[go: up one dir, main page]

WO2019111160A1 - Formes cristallines de succinate de ribociclib - Google Patents

Formes cristallines de succinate de ribociclib Download PDF

Info

Publication number
WO2019111160A1
WO2019111160A1 PCT/IB2018/059641 IB2018059641W WO2019111160A1 WO 2019111160 A1 WO2019111160 A1 WO 2019111160A1 IB 2018059641 W IB2018059641 W IB 2018059641W WO 2019111160 A1 WO2019111160 A1 WO 2019111160A1
Authority
WO
WIPO (PCT)
Prior art keywords
ribociclib succinate
ribociclib
crystalline form
succinate
hours
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/IB2018/059641
Other languages
English (en)
Inventor
Anu Arya
Chandra Has Khanduri
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Sun Pharmaceutical Industries Ltd
Original Assignee
Sun Pharmaceutical Industries Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Sun Pharmaceutical Industries Ltd filed Critical Sun Pharmaceutical Industries Ltd
Publication of WO2019111160A1 publication Critical patent/WO2019111160A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention relates to crystalline Forms S 1 and S2 of ribociclib succinate, processes for their preparation, pharmaceutical compositions comprising these crystalline forms, and their use for the treatment of postmenopausal women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer.
  • HR hormone receptor
  • HER2 human epidermal growth factor receptor 2
  • Ribociclib succinate chemically is butanedioic acid-7-cyclopentyl-N, N-dimethyl- 2- ⁇ [5 -(piperazin- 1 -yl) pyridin-2-yl]amino ⁇ -7H-pyrrolo [2,3 -d]pyrimidine-6-carboxamide
  • Ribociclib is a kinase inhibitor which is approved in United States as ribociclib succinate for use in combination with an aromatase inhibitor, as an initial endocrine -based therapy for the treatment of postmenopausal women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2) -negative advanced or metastatic breast cancer.
  • HR hormone receptor
  • HER2 human epidermal growth factor receptor 2
  • U.S. Patent No. 8,415,355 describes a process for the preparation of ribociclib.
  • U.S. Patent No. 9,193,732 discloses crystalline forms of ribociclib succinate and processes thereof.
  • PCT Publication No. W02016/0091221 discloses crystalline Form A of ribociclib hemi-succinate and crystalline Form I of ribociclib monosuccinate and their processes.
  • the present invention relates to crystalline Forms S 1 and S2 of ribociclib succinate, processes for their preparation, pharmaceutical compositions comprising these crystalline forms, and their use for the treatment of postmenopausal women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer.
  • the crystalline Forms S 1 and S2 of ribociclib succinate of the present invention are stable.
  • Figure 1 depicts an X-Ray Powder Diffraction (XRPD) pattern of crystalline Form Sl of ribociclib succinate.
  • Figure 2 depicts a Differential Scanning Calorimetry (DSC) thermogram of crystalline Form Sl of ribociclib succinate.
  • Figure 3 depicts an Infra-red (IR) spectrum of crystalline Form Sl of ribociclib succinate.
  • FIG. 4 depicts Thermogravimetric analysis (TGA) of crystalline Form Sl of ribociclib succinate.
  • Figure 5 depicts an X-Ray Powder Diffraction (XRPD) pattern of crystalline Form S2 of ribociclib succinate.
  • Figure 6 depicts a Differential Scanning Calorimetry (DSC) thermogram of crystalline Form S2 of ribociclib succinate.
  • Figure 7 depicts an Infra-red (IR) spectrum of crystalline Form S2 of ribociclib succinate.
  • ambient temperature refers to the temperature in the range of 25 °C to 35°C.
  • contacting refers to dissolving, slurrying, stirring, suspending, or combinations thereof.
  • a first aspect of the present invention provides a crystalline Form Sl of ribociclib succinate.
  • the crystalline Form S 1 of ribociclib succinate is characterized by an X-ray powder diffraction (XRPD) pattern having peaks at d-spacing’s of about 6.8, 4.7, 4.4, 4.2, 3.9 A, and further characterized by additional peaks at d-spacing’s of about 8.1, 6.5, 4.2, 4.0, and 3.0 A.
  • the present invention provides for crystalline form Sl in the form of hydrates, non-hydrates or mixtures thereof.
  • the crystalline Form S 1 of ribociclib succinate is characterized by a differential scanning calorimetry (DSC) thermogram having an endothermic peak at about 212.2°C.
  • the crystalline Form S 1 of ribociclib succinate is characterized by an XRPD pattern substantially as depicted in Figure 1, a DSC thermogram substantially as depicted in Figure 2, an IR absorption spectrum substantially as depicted in Figure 3, or a TGA substantially as depicted in Figure 4.
  • a second aspect of the present invention provides a process for the preparation of the crystalline Form Sl of ribociclib succinate comprising contacting ribociclib succinate with a solvent.
  • Ribociclib succinate to be used as a starting material, for the preparation of the crystalline Form S 1 of ribociclib succinate may be obtained by methods known in the literature such as those disclosed in U.S. Patent No. 9,193,732.
  • water may be added with the solvent.
  • seeding may be carried out with crystal seed of the crystalline Form Sl of ribociclib succinate.
  • Crystalline Form Sl of ribociclib succinate is prepared by contacting ribociclib succinate with a solvent.
  • the solvent is selected from alcohols, sulfoxides, ketones, nitriles, aromatic hydrocarbons, ethers, water mixtures thereof.
  • the solvent may also be selected from mixture of these solvents with water.
  • alcohols include ethanol, n-propanol, iso-propanol, n-butanol, sec-butanol, tert-butanol, and n-pentanol.
  • the solvent is selected from mixture of alcohol and water.
  • the solvent is selected from alcohols, water, and mixtures thereof.
  • sulfoxide is dimethylsulfoxide.
  • ketones include acetone, methyl ethyl ketone, and methyl isobutyl ketone.
  • nitrile is acetonitrile.
  • aromatic hydrocarbon include toluene and xylene.
  • ethers include methyl tert- butyl ether, tetrahydrofuran, l,4-dioxane, ethyl methyl ether, diethyl ether, diisopropyl ether, and anisole.
  • ribociclib succinate is contacted with an alcohol solvent. In another embodiment, ribociclib succinate is contacted with n-propanol. In a preferred embodiment, ribocilcib succinate is contacted with a mixture of n-propanol and water. In another embodiment, ribociclib succinate is contacted with iso-propanol. In a preferred embodiment, ribociclib succinate is contacted with a mixture of iso-propanol and water. In another embodiment, ribociclib succinate is contacted with ethanol. In a preferred embodiment, ribociclib succinate is contacted with a mixture of ethanol and water.
  • ribociclib succinate is contacted with sec-butanol. In a preferred embodiment, ribociclib succinate is contacted with a mixture of sec-butanol and water. In another embodiment, ribociclib succinate is contacted with n-butanol. In a preferred embodiment, ribociclib succinate is contacted with a mixture of n-butanol and water. In another embodiment, ribociclib succinate is contacted with tert-butanol. In a preferred embodiment, ribociclib succinate is contacted with a mixture of tert-butanol and water. In another embodiment, ribociclib succinate is contacted with a sulfoxide solvent.
  • ribociclib succinate is contacted with dimethylsulfoxide. In another embodiment, ribociclib succinate is contacted with a mixture of a sulfoxide and a nitrile solvent. In a preferred embodiment, ribociclib succinate is contacted with a mixture of dimethylsulfoxide and acetonitrile. In another embodiment, ribociclib succinate is contacted with a ketone solvent. In another embodiment, ribociclib succinate is contacted with acetone. In a preferred embodiment, ribociclib succinate is contacted with a mixture of acetone and water. In another embodiment, ribociclib succinate is contacted with methyl ethyl ketone.
  • ribociclib succinate is contacted with a mixture of methyl ethyl ketone and water. In another embodiment, ribociclib succinate is contacted with methyl isobutyl ketone. In a preferred embodiment, ribociclib succinate is contacted with a mixture of methyl isobutyl ketone and water. In another embodiment, ribociclib succinate is contacted with anisole. In a preferred embodiment, ribociclib succinate is contacted with a mixture of anisole and water. In another embodiment, ribociclib succinate is contacted with a nitrile solvent. In another embodiment, ribociclib succinate is contacted with acetonitrile.
  • ribociclib succinate is contacted with a mixture of acetonitrile and water. In another embodiment, ribociclib succinate is contacted with an aromatic hydrocarbon solvent. In another embodiment, ribociclib succinate is contacted with toluene. In a preferred embodiment, ribociclib succinate is contacted with a mixture of toluene and water. In another embodiment, ribociclib succinate is contacted with an ether solvent. In another embodiment, ribociclib succinate is contacted with tetrahydrofuran. In a preferred embodiment, ribociclib succinate is contacted with a mixture of tetrahydrofuran and water.
  • the amount of solvent is 30 fold to 60 fold (v/w) with respect to ribociclib succinate. In another embodiment, the amount of solvent is 35 fold to 60 fold (v/w) with respect to ribociclib succinate. In another embodiment, the amount of solvent is 45 fold to 55 fold (v/w) with respect to ribociclib succinate. In another embodiment, the amount of solvent is 50 fold to 55 fold (v/w) with respect to ribociclib succinate.
  • the amount of water is 0.1 fold to 0.5 fold (v/w) with respect to ribociclib succinate. In another embodiment, the amount of water is 0.2 fold to 0.45 fold (v/w) with respect to ribociclib succinate. In a preferred embodiment, the amount of water is 0.15 fold to 0.35 fold (v/w) with respect to ribociclib succinate.
  • the volume ratio of solvent to water is between 100: 1 to 20: 1.
  • the volume ratio of solvent to water is between 50: 1 to 25: 1. In another embodiment, the volume ratio of solvent to water is between 40: 1 to 33 : 1.
  • Ribociclib succinate is contacted with the solvent at ambient temperature to the reflux temperature of the solvent. In one embodiment, ribociclib succinate is contacted with the solvent at a temperature of about 65°C to about 80°C. In another embodiment, ribociclib succinate is contacted with the solvent at a temperature of about 70°C to about 78°C. In a preferred embodiment, ribociclib succinate is contacted with the solvent at reflux temperature .
  • Ribociclib succinate is contacted with the solvent for about 2 hours to about 10 hours. In an embodiment, ribociclib succinate is contacted with the solvent for about 2.5 hours to about 7 hours. In a preferred embodiment, ribociclib succinate is contacted with the solvent for about 2.5 hours to about 4.5 hours.
  • Crystalline Form S 1 of ribociclib succinate may be dried using conventional techniques, for example, drying, drying under vacuum, spray drying, suck drying, air drying, or agitated thin film drying.
  • Drying may be carried out using any suitable method, such as, drying under reduced pressure, air drying, or vacuum tray drying. In a preferred embodiment, drying is carried out at high temperature under reduced pressure. In another embodiment, air drying is carried out. In another embodiment, vacuum tray drying is carried out. In another embodiment, drying is carried out at a temperature of about 45°C to about 70°C. In another embodiment, drying is carried out at a temperature of about 50°C to about 60°C.
  • drying is carried out at a temperature of about 50°C to about 55°C.
  • Drying is carried out for a period of about 5 hours to about 16 hours. In one embodiment, drying is carried out for about 16 hours. In a preferred embodiment, drying is carried out for about 10 hours. In yet another preferred embodiment, drying is carried out for about 9 hours. In yet another preferred embodiment, drying is carried out for about 12 hours. In another embodiment, drying is carried out for about 6.5 hours. In another embodiment, drying is carried out for about 6 hours. In another embodiment, drying is carried out for about 5 hours.
  • the dried material may optionally be micronized.
  • micronization is carried out using ball mill.
  • micronization is carried out using colloid mill.
  • micronization is carried out using grinding mill.
  • micronization is carried out using air jet mill.
  • micronization is carried out using roller mill.
  • micronization is carried out using impact mill.
  • a third aspect of the present invention provides a process for the preparation of a crystalline Form S 1 of ribociclib succinate comprising contacting ribociclib free base with succinic acid in the presence of a solvent.
  • Ribociclib free base to be used as a starting material, for the preparation of crystalline Form S 1 of ribociclib succinate may be obtained by methods known in the literature such as those disclosed in U.S. Patent No. 8,415,355.
  • seeding may be carried out with crystal seed of Form Sl .
  • Crystalline Form S 1 of ribociclib succinate is prepared by contacting ribociclib free base with succinic acid in the presence of a solvent.
  • the solvent is selected from alcohols, water, and mixtures thereof. Examples of alcohols include ethanol, n-propanol, iso-propanol, n-butanol, iso-butanol, tert-butanol, and n-pentanol.
  • ribociclib free base is contacted with an alcohol solvent.
  • ribociclib free base is contacted with iso-propanol.
  • ribociclib free base is contacted with a mixture of iso-propanol and water.
  • the amount of solvent is 30 fold to 60 fold (v/w) with respect to ribociclib free base. In another embodiment, the amount of solvent is 35 fold to 60 fold (v/w) with respect to ribociclib free base. In another embodiment, the amount of solvent is 45 fold to 55 fold (v/w) with respect to ribociclib free base. In another embodiment, the amount of solvent is 50 fold to 55 fold (v/w) with respect to ribociclib free base.
  • Ribociclib free base is contacted with the solvent at ambient temperature to a temperature of about 66°C to about 80°C. In an embodiment, ribociclib free base is contacted with the solvent at ambient temperature. In another embodiment, ribociclib free base is contacted with the solvent at a temperature of about 70°C to about 75°C.
  • Ribociclib free base is contacted with the solvent for about 10 minutes to about 60 minutes. In another embodiment, ribociclib free base is contacted with the solvent for about 20 minutes to about 40 minutes. In another embodiment, ribociclib free base is contacted with the solvent for about 25 minutes to about 30 minutes.
  • the solution of ribociclib free base in the solvent is further treated with succinic acid at a temperature of about 65°C to about 80°C.
  • the solution of ribociclib free base in the solvent is treated with succinic acid at a temperature of about 70°C to about 75°C.
  • the solution of ribociclib free base with succinic acid is further stirred at ambient temperature for about 2 hours to about 20 hours. In a preferred embodiment, the solution of ribociclib free base with succinic acid is stirred for about 3 hours. In another preferred embodiment, the solution of ribociclib free base with succinic acid is stirred for about 6 hours. In another preferred embodiment, the solution of ribociclib free base with succinic acid is stirred for about 16 hours.
  • Isolation of crystalline Form S 1 of ribociclib succinate may optionally be carried out by filtration, decantation, extraction, distillation, evaporation, chromatography, precipitation, concentration, crystallization, centrifugation, or recrystallization.
  • Crystalline Form S 1 of ribociclib succinate may be dried using conventional techniques, for example, drying, drying under vacuum, spray drying, suck drying, air drying, or agitated thin film drying.
  • Drying may be carried out using any suitable method, such as, drying under reduced pressure, air drying, or vacuum tray drying. In one embodiment, drying is carried out at high temperature under reduced pressure. In another embodiment, air drying is carried out. In another embodiment, vacuum tray drying is carried out. In another embodiment, drying is carried out at a temperature of about 45°C to about 70°C. In another embodiment, drying is carried out at a temperature of about 50°C to about 60°C. In another embodiment, drying is carried out at a temperature of about 50°C to about 55°C.
  • any suitable method such as, drying under reduced pressure, air drying, or vacuum tray drying. In one embodiment, drying is carried out at high temperature under reduced pressure. In another embodiment, air drying is carried out. In another embodiment, vacuum tray drying is carried out. In another embodiment, drying is carried out at a temperature of about 45°C to about 70°C. In another embodiment, drying is carried out at a temperature of about 50°C to about 60°C. In another embodiment, drying is carried out at a temperature of about 50°C to about
  • Drying is carried out for a period of about 5 hours to about 16 hours. In one embodiment, drying is carried out for about 16 hours. In another embodiment, drying is carried out for about 10 hours. In another embodiment, drying is carried out for about 9 hours. In another embodiment, drying is carried out for about 6.5 hours. In another embodiment, drying is carried out for about 6 hours. In another embodiment, drying is carried out for about 5 hours.
  • the dried material may optionally be micronized.
  • micronization is carried out using ball mill.
  • micronization is carried out using colloid mill.
  • micronization is carried out using grinding mill.
  • micronization is carried out using air jet mill.
  • micronization is carried out using roller mill.
  • micronization is carried out using impact mill.
  • Crystalline form Sl of ribociclib succinate is non-hygroscopic in nature. Crystalline form Sl of ribociclib succinate has a purity of more than 98% as determined by High Performance Liquid Chromatography.
  • a fourth aspect of the present invention provides a crystalline Form S2 of ribociclib succinate.
  • the crystalline Form S2 of ribociclib succinate is characterized by an X-ray powder diffraction (XRPD) pattern having peaks at d-spacings of about 4.8, 4.7, 4.2, and 4.0 A, and further characterized by additional peaks at d-spacings of about 9.5, 4.4, 3.9, 3.8, and 3.5 A.
  • XRPD X-ray powder diffraction
  • the crystalline Form S2 of ribociclib succinate is characterized by a differential scanning calorimetry (DSC) thermogram having endothermic peaks at about 88.4°C, 149. l°C, and l85.7°C.
  • DSC differential scanning calorimetry
  • Crystalline Form S2 of ribociclib succinate is characterized by an XRPD pattern substantially as depicted in Figure 5, a DSC thermogram substantially as depicted in Figure 6, or an IR absorption spectrum substantially as depicted in Figure 7.
  • a fifth aspect of the present invention provides a process for the preparation of a crystalline Form S2 of ribociclib succinate comprising contacting ribociclib succinate with methanol.
  • Ribociclib succinate to be used as a starting material, for the preparation of crystalline Form S2 of ribociclib succinate may be obtained by methods known in the literature such as those disclosed in U.S. Patent No. 9,193,732.
  • water may be added with methanol.
  • seeding may be carried out with crystal seed of Form S2.
  • Ribociclib succinate is contacted with methanol at ambient temperature to a temperature of about 65°C to 80°C. In an embodiment, ribociclib succinate is contacted with methanol at a temperature of about 70°C to about 75 °C.
  • the solution of ribociclib succinate in methanol is further stirred at ambient temperature for about one hour to about 15 hours. In one embodiment, the solution of ribociclib succinate in methanol is stirred for about 6 hours. In another embodiment, the solution of ribociclib succinate in methanol is stirred for about 4 hours. In another embodiment, the solution of ribociclib succinate in methanol is stirred for about 2 hours. In another embodiment, the solution of ribociclib succinate in methanol is stirred for about one hour.
  • Isolation of crystalline Form S2 of ribociclib succinate may optionally be carried out by filtration, decantation, extraction, distillation, evaporation, chromatography, precipitation, concentration, crystallization, centrifugation, or recrystallization.
  • Crystalline Form S2 of ribociclib succinate may be dried using conventional techniques, for example, drying, drying under vacuum, spray drying, suck drying, air drying, or agitated thin film drying.
  • Drying may be carried out using any suitable method, such as, drying under reduced pressure, air drying, or vacuum tray drying. In a preferred embodiment, drying is carried out at high temperature under reduced pressure. In another embodiment, air drying is carried out. In another embodiment, vacuum tray drying is carried out. In a preferred embodiment, drying is carried out at a temperature of about 35°C to about 60°C under reduced pressure. In another embodiment, drying is carried out at a temperature of about 40°C to about 45 °C under reduced pressure.
  • Drying is carried out for a period of about 5 hours to about 16 hours. In a preferred embodiment, drying is carried out for about 12 hours. In another embodiment, drying is carried out for about 9 hours. In another embodiment, drying is carried out for about 6 hours. In another embodiment, drying is carried out for about 4 hours.
  • the dried material may optionally be micronized.
  • micronization is carried out using ball mill.
  • micronization is carried out using colloid mill.
  • micronization is carried out using grinding mill.
  • micronization is carried out using air jet mill.
  • micronization is carried out using roller mill.
  • micronization is carried out using impact mill.
  • a sixth aspect of the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising crystalline Forms Sl or S2 of ribociclib succinate, and one or more pharmaceutically acceptable carriers, diluents, or excipients.
  • a seventh aspect of the present invention provides a method of treating postmenopausal women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer comprising administering to a patient in need thereof a therapeutically effective amount of a composition comprising crystalline Forms Sl or S2 of ribociclib succinate.
  • HR hormone receptor
  • HER2 human epidermal growth factor receptor 2
  • XRPD of the sample was determined by using a PANalytical ® instrument; Model X’pert PRO; Detector: X’celerator ® .
  • DSC of the sample was recorded using a Mettler-Toledo ® 82 le instrument or Shematzu; DTG-60-A instrument.
  • TGA was recorded using a TA Q-500 instrument.
  • Ribociclib succinate 200 mg was added to a mixture of iso-propanol (10 mL) and water (100 pL) to obtain a slurry. The slurry was heated at 70°C for 2 hours to obtain a reaction mixture. The reaction mixture was stirred at ambient temperature for 16 hours to obtain a solid. The solid obtained was collected by filtration and then dried at 50°C under vacuum for 12 hours to obtain the title compound.
  • Method B Ribociclib succinate (400 mg) was added to a mixture of ethanol (4 mL) and water (100 pL) to obtain a slurry. The slurry was heated at 70°C for 2 hours to obtain a reaction mixture. The reaction mixture was stirred at ambient temperature for 5 hours to obtain a solid. The solid obtained was collected by filtration and then dried at 50°C under vacuum for 5 hours to obtain the title compound.
  • Method D Ribociclib succinate (400 mg) was added to a mixture of n-butanol (4 mL) and water (150 pL) to obtain a slurry. The slurry was heated at 70°C for 2.5 hours to obtain a reaction mixture. The reaction mixture was stirred at ambient temperature for 15 hours to obtain a solid. The solid obtained was collected by filtration and then dried at 50°C under vacuum for 6.5 hours to obtain the title compound.
  • Method F Ribociclib succinate (400 mg) was added to a mixture of n-propanol (5 mL) and water (150 pL) to a obtain slurry. The slurry was heated at 70°C for 2.5 hours to obtain a reaction mixture. The reaction mixture was stirred at ambient temperature for 4 hours to obtain a solid. The solid obtained was collected by filtration and then dried at 50°C under vacuum for 9 hours to obtain the title compound.
  • Method H Ribociclib succinate (400 mg) was added to a mixture of acetone (5 mL) and water (100 pL) to obtain a slurry. The slurry was heated at 70°C for 4 hours to obtain a reaction mixture. The reaction mixture was stirred at ambient temperature for 15 hours to obtain a solid. The solid obtained was collected by filtration and then dried at 50°C under vacuum for 6.5 hours to obtain the title compound.
  • Method K Ribociclib succinate (400 mg) was added to a mixture of acetonitrile (5 mL) and water (100 pL) to obtain slurry. The slurry was heated at 70°C for 4 hours to obtain a reaction mixture. The reaction mixture was stirred at ambient temperature for 1 hour to obtain a solid. The solid obtained was collected by filtration and then dried at 50°C under vacuum for 6.5 hours to obtain the title compound.
  • Method L Ribociclib succinate (400 mg) was added to a mixture of toluene (5 mL) and water (150 pL) to obtain a slurry. The slurry was heated at 70°C for 4.5 hours to obtain a reaction mixture. The reaction mixture was stirred at ambient temperature for 15 hours to obtain a solid. The solid obtained was collected by filtration and then dried at 50°C under vacuum for 10 hours to obtain the title compound.
  • Method N Ribociclib succinate (400 mg) was added to a mixture of tetrahydrofiiran (5 mL) and water (150 pL) to obtain a slurry. The slurry was heated at 70°C for 2.5 hours to obtain a reaction mixture. Tetrahydrofiiran (5 mL) and water (50 pL) were again added to the reaction mixture and stirred at 65°C for 4 hours to obtain a solid. The solid obtained was collected by filtration and then dried at 50°C under vacuum for 9 hours to obtain the title compound.
  • Method P Ribociclib free base (500 mg) was added to iso-propanol (30 mL) and stirred at 75°C for 25 minutes to obtain a reaction mixture.
  • Iso-propanol (2.5 mL) with succinic acid (150 mg) was added to the reaction mixture and stirring was continued at 75° C for 4 hours.
  • Iso-propanol (10 mL) was again added to the reaction mixture and the mixture was stirred at ambient temperature for 12 hours to obtain a solid. The solid obtained was collected by filtration and then dried at 50°C under vacuum for 10 hours to obtain the title compound.
  • Table 1 provides the d-spacing values (A), the corresponding 20 values, and the relative intensity of crystalline Form S 1 of ribociclib succinate as prepared by Method R.
  • Crystalline Form S l of ribociclib succinate is characterized by an XRPD pattern substantially as depicted in Figure 1, a DSC thermogram substantially as depicted in Figure 2, an IR absorption spectrum substantially as depicted in Figure 3, or a TGA substantially as depicted in Figure 4.
  • the crystalline form S l was found to be stable for 6 months when subjected to a stability testing_at various temperature and relative humidity' (RH) conditions, for example, at 25 ⁇ 2°C/ 60 ⁇ 5%RH, 30 ⁇ 2°C/ 55 ⁇ 5%RH, and 40 ⁇ 2°C/ 75 ⁇ 5% RH.
  • Stability testing in the present invention was carried out using triple pouch packing i.e., inner pouch (low- density polyethylene (LDPE) twisted and tied), middle pouch (poiyester/LDPE heat sealed under vacuum with silica gel sachet) and outer pouch (polyester film/aluminum foil/LDPE heat sealed). The results are depicted in Table 3
  • Table 2 provides the d-spacing values (A), the corresponding 2Q values, and the relative intensity of crystalline Form S2 of ribociclib succinate as prepared by method A.
  • Crystalline Form S2 of ribociclib succinate is characterized by an XRPD pattern substantially as depicted in Figure 5, a DSC thermogram substantially as depicted in Figure 6, or an IR absorption spectrum substantially as depicted in Figure 7.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Oncology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

La présente invention concerne des formes cristallines S1 et S2 de succinate de ribociclib, des procédés pour leur préparation, une composition pharmaceutique comprenant ces formes cristallines, et leur utilisation pour le traitement de femmes post-ménopausées avec un récepteur hormonal (HR) positif, le récepteur 2 du facteur de croissance épidermique humain (HER2)-négatif avancé ou le cancer du sein métastatique.
PCT/IB2018/059641 2017-12-04 2018-12-04 Formes cristallines de succinate de ribociclib Ceased WO2019111160A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN201711043345 2017-12-04
IN201711043345 2017-12-04

Publications (1)

Publication Number Publication Date
WO2019111160A1 true WO2019111160A1 (fr) 2019-06-13

Family

ID=66751337

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2018/059641 Ceased WO2019111160A1 (fr) 2017-12-04 2018-12-04 Formes cristallines de succinate de ribociclib

Country Status (1)

Country Link
WO (1) WO2019111160A1 (fr)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3231805B1 (fr) 2014-12-12 2020-03-04 Crystal Pharmatech Co. Ltd. Sel de composé de pyrrolo[2,3-d]pyrimidine et nouveau polymorphe de sel
US10611772B2 (en) 2018-07-02 2020-04-07 Apotex Inc. Crystalline form of Ribociclib succinate
WO2020152629A1 (fr) * 2019-01-23 2020-07-30 Novartis Ag Nouvelles formes cristallines d'un sel de succinate de diméthylamide d'acide 7-cyclopentyl-2-(5-pipérazin-1-yl-pyridin-2-ylamino)-7h-pyrrolo[2,3-d]pyrimidine-6-carboxylique
US20220204514A1 (en) * 2019-04-29 2022-06-30 Msn Laboratories Private Limited, R&D Center Polymorphs of 7-cyclopentyl-n,n-dimethyl-2-{[5-(piperazin-1-yl) pyridin-2-yl]-amino}-7h-pyrrolo[2,3-d]pyrimidine-6-carboxamide and its pharmaceutically acceptable salts and process for the preparation thereof
WO2025203051A1 (fr) * 2024-03-28 2025-10-02 Cipla Limited Forme c de succinate de ribociclib et son procédé de préparation

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20130217698A1 (en) * 2010-11-10 2013-08-22 Astex Therapeutics Ltd Salt(s) of 7-cyclopentyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-7h-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide and processes of making thereof
WO2016155670A1 (fr) * 2015-04-01 2016-10-06 苏州晶云药物科技有限公司 Inhibiteur de cdk, cristal eutectique d'inhibiteur de mek, et leur procédé de préparation
US20170342075A1 (en) * 2014-12-12 2017-11-30 Crystal Pharmatech Co., Ltd. Salt of Pyrrolo[2,3-D]pyrimidine Compound and Novel Polymorph of Salt

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20130217698A1 (en) * 2010-11-10 2013-08-22 Astex Therapeutics Ltd Salt(s) of 7-cyclopentyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-7h-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide and processes of making thereof
US20170342075A1 (en) * 2014-12-12 2017-11-30 Crystal Pharmatech Co., Ltd. Salt of Pyrrolo[2,3-D]pyrimidine Compound and Novel Polymorph of Salt
WO2016155670A1 (fr) * 2015-04-01 2016-10-06 苏州晶云药物科技有限公司 Inhibiteur de cdk, cristal eutectique d'inhibiteur de mek, et leur procédé de préparation

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
BURKI: "Ribociclib in HR -positive, HER2-negative Breast Cancer", THE LANCET, vol. 17, 2016, pages e482 *

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3231805B1 (fr) 2014-12-12 2020-03-04 Crystal Pharmatech Co. Ltd. Sel de composé de pyrrolo[2,3-d]pyrimidine et nouveau polymorphe de sel
US10611772B2 (en) 2018-07-02 2020-04-07 Apotex Inc. Crystalline form of Ribociclib succinate
WO2020152629A1 (fr) * 2019-01-23 2020-07-30 Novartis Ag Nouvelles formes cristallines d'un sel de succinate de diméthylamide d'acide 7-cyclopentyl-2-(5-pipérazin-1-yl-pyridin-2-ylamino)-7h-pyrrolo[2,3-d]pyrimidine-6-carboxylique
JP2022517842A (ja) * 2019-01-23 2022-03-10 ノバルティス アーゲー ７－シクロペンチル－２－（５－ピペラジン－１－イル－ピリジン－２－イルアミノ）－７Ｈ－ピロロ［２，３－ｄ］ピリミジン－６－カルボン酸ジメチルアミドのコハク酸塩の新規な結晶形態
AU2023200724B2 (en) * 2019-01-23 2025-01-23 Novartis Ag New crystalline forms of a succinate salt of 7-cyclopentyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-7h-pyrrolo[2,3-d]pyrimidine -6-carboxylic acid dimethylamide
IL284510B1 (en) * 2019-01-23 2025-06-01 Novartis Ag New crystalline forms of a succinate salt of 7-cyclopentyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-7h-pyrrolo[2,3-d]pyrimidine -6-carboxylic acid dimethylamide
US12390468B2 (en) 2019-01-23 2025-08-19 Novartis Ag Crystalline forms of a succinate salt of 7-cyclopentyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide
IL284510B2 (en) * 2019-01-23 2025-10-01 Novartis Ag Crystalline forms of succinate salt of 7-cyclopentyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-h7-pyrrolo[3,2-d]pyrimidine-6-carboxylic acid dimethylamide
US20220204514A1 (en) * 2019-04-29 2022-06-30 Msn Laboratories Private Limited, R&D Center Polymorphs of 7-cyclopentyl-n,n-dimethyl-2-{[5-(piperazin-1-yl) pyridin-2-yl]-amino}-7h-pyrrolo[2,3-d]pyrimidine-6-carboxamide and its pharmaceutically acceptable salts and process for the preparation thereof
US12473292B2 (en) * 2019-04-29 2025-11-18 Msn Laboratories Private Limited, R&D Center Polymorphs of 7-cyclopentyl-N,N-dimethyl-2-{[5-(piperazin-1-yl) pyridin-2-yl]-amino}-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide and its pharmaceutically acceptable salts and process for the preparation thereof
WO2025203051A1 (fr) * 2024-03-28 2025-10-02 Cipla Limited Forme c de succinate de ribociclib et son procédé de préparation

Similar Documents

Publication Publication Date Title
WO2019111160A1 (fr) Formes cristallines de succinate de ribociclib
EP3337485B1 (fr) Formes cristallines d'ibrutinib
WO2017203514A9 (fr) Polymorphes de crisaborole et procédés pour les produire
CA2767489A1 (fr) Forme cristalline du posaconazole
JP2015516425A (ja) ６−ｏ−（４−ジメチルアミノエトキシ）シンナモイルフマギロールのシュウ酸塩の多形塩ならびにその製造および使用方法
WO2017107972A1 (fr) Nouvelle forme cristalline d'agoniste sélectif du récepteur s1p1 et son procédé de préparation
WO2019019959A1 (fr) Forme cristalline d'un monosuccinate de ribociclib et procédé de préparation et utilisation de ce dernier
WO2012150561A1 (fr) Solvate de diméthylformamide rifaximine
WO2016090257A1 (fr) Sels et forme cristallines de 6-acétyl-8-cyclopentyl-5-méthyl-2((5-(pipérazin-1-yl) pyridin-2-yl)amino)pyrido [2,3-d] pyrimidin -7 (8h)-one (palbociclib)
JP2020528057A (ja) ビランテロールトリフェニル酢酸塩の新規な結晶形態及びこれらの調製プロセス
CA2984961C (fr) Sel de sodium d'inhibiteur de transporteur d'acide urique et sa forme cristalline
CN113795484B (zh) 共晶型艾氟康唑及其制备方法
CN110372635B (zh) 氢溴酸沃替西汀α晶型的制备方法
CN114478679A (zh) 双氢青蒿素-熊去氧胆酸缀合物的多晶型物及其制备方法和应用
JP6761564B2 (ja) ナトリウム・グルコース共輸送体２阻害薬のｌ−プロリン化合物、およびｌ−プロリン化合物の一水和物および結晶
CN107021917B (zh) 哌马色林半酒石酸盐的新晶型及其制备方法
CN108026043A (zh) 一种萘环化合物的晶型
CN106336363B (zh) 一种沙芬酰胺甲磺酸盐晶型c及其制备方法
EP3004101A1 (fr) Forme cristalline de n,n-dicyclopropyl-4-(1,5-diméthyl-1h-pyrazol-3-ylamino)-6-éthyl-1-méthyl-1,6-dihydro-imidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide pour le traitement de troubles myéloprolifératifs
WO2014193866A1 (fr) Forme cristalline du n,n-dicyclopropyl-4-(1,5-diméthyl-1h-pyrazol-3-ylamino)-6-éthyl-1-méthyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide pour traiter les maladies myéloprolifératives
CN110964017A (zh) 瑞博西尼单琥珀酸盐的多晶型物及其制备方法和用途
WO2014147641A2 (fr) Sel de phosphate de sitagliptine et de ptérostilbène, son procédé de préparation et composition pharmaceutique en contenant
CN101384584A (zh) 贝西吡啶盐酸盐的晶型、制备方法及其应用
CN110577494B (zh) 苯并咪唑衍生物的多晶型物及其制备方法和用途
WO2024023796A1 (fr) Polymorphes, co-cristaux et solvates de fruquintinib, leurs procédés de préparation et leur utilisation

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 18885073

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 18885073

Country of ref document: EP

Kind code of ref document: A1